Obesity is a recognized health problem which is associated with cardiovascular disease, diabetes and certain forms of cancer. It is well established that although disciplined dieting may result in weight loss, such weight loss is rarely long lasting due to two distinctive effects which are associated with dieting. These effects are a notable increase in hunger, or drive to eat, and a notable decrease in the basal metabolic rate of the dieting individual. Thus, a frequent consequence of dieting with low caloric intake is an increase in weight gain or rebound effect in weight gain to or beyond the original pre-diet weight due to increased hunger and a concomitant reduction in basal metabolic rate following termination of the low caloric diet.
Obesity most commonly arises as a result of the imbalance of caloric intake (eating) vs. caloric expenditure. However, the propensity to become obese may be affected by certain genes and, in addition, certain metabolic disorders have a direct effect on weight gain, for example, growth hormone deficiency or hypothyroidism. Regardless of the underlying physiological cause of obesity, appetite regulation is a key factor in controlling weight gain and maintenance of body weight.
Recent scientific advances in cellular and molecular endocrinology, neurobiology, and physiology have greatly expanded the understanding of the complex hormonal and neural pathways regulating body weight and appetite. It is now clear that neural and hormonal systems interact at virtually every step in feeding satiety and metabolic control. Central to this new understanding has been the recognition of the roles subserved by key neural systems operating within the brain, specifically within the hypothalamus.
Of the many systems acting within the hypothalamus to regulate appetite and metabolism is neuropeptide Y (NPY) which is now recognized to play a pivotal role. NPY is a 36 amino acid peptide secreted by hypothalamic neurons and is the most potent (on a molar basis) naturally occurring substance yet discovered that stimulates appetite. NPY belongs to a family of neuroendocrine peptides including pancreatic polypeptide and peptide YY. Interestingly, both the amino acid sequence of NPY and the location of NPY-expressing neurons within the brain have been highly evolutionarily conserved, evidencing that the physiological role of hypothalamic NPY is universal among vertebrates (D. Larhammar, "Evolution of neuropeptide Y, peptide YY and pancreatic polypeptide," Regulatory Peptides, 62:1-11 (1996)). NPY, when administered into the brain, causes a long-lasting increase of food intake and when given chronically, results in development of obesity reviewed in White, "Neuropeptide Y: a central regulator of energy homeostasis," Regulatory Peptides, 49:93-107 (1993). Similarly, high levels of NPY are observed specifically in the hypothalamus of obese animals (Sanacora et al., "Increased hypothalamic content of preproneuropeptide Y messenger ribonucleic acid in genetically obese Zucker rats and its regulation by food deprivation," Endocrinology, 127:730-737 (1990); Sanacora et al., "Developmental aspect of differences in hypothalamic preproneuropeptide Y messenger ribonucleic acid content in lean and genetically obese Zucker rats," J Neuroendocrinol., 4:353-357 (1990)); and food deprived or food restricted animals (White and Kershaw, "Increased hypothalamic neuropeptide Y expression following food deprivation," Molec. Cell. Neurosci., 1:41-48 (1990); Sahu, et al. "Hypothalamic preproNPY mRNA levels in rats subjected to a scheduled feeding regimen," Molecular Brain Research, 15:15-18 (1992)). As these studies predict, reduction in hypothalamic NPY levels is associated with reduced food intake.
In summary, secretion of NPY from neurons within the hypothalamus stimulates feeding and chronically high levels of NPY expression result in hyperphagia and obesity. The ability to reduce high levels of NPY results in the diminution of the drive to eat. NPY gene regulation and physiology are reviewed in Berelowitz et al., "Regulation of hypothalamic neuropeptide expression by peripheral metabolism," TEM 3:127-133 (1992), the disclosure of which is herein incorporated by reference.
Growth hormone releasing factor (GRF), also called growth hormone releasing hormone (GHRH), is a 44 amino acid peptide of the glucagon-VIP-PHI family and is present in high concentration in the hypothalamus, particularly in the arcuate nucleus and medium eminence. GRF is the primary stimulatory factor controlling synthesis and secretion of pituitary growth hormone (GH), a critical regulatory hormone of metabolic homeostasis controlling breakdown of fat (lipolysis) and synthesis of protein. Thus a normal level of GRF is required for appropriate levels of GH to maintain muscle mass while promoting lipolysis (Berelowitz et al. (1992), supra).
The relationship between hypothalamic levels of GRF and food deprivation is the opposite of that observed with NPY. Specifically, levels of GRF are reduced in the hypothalamus following food deprivation (White et al., "Localization of prepro-growth hormone releasing factor mRNA in rat brain and regulation of its content by food deprivation and experimental diabetes," Molec. Cell. Neurosci., 1:183-192 (1990); Bruno et al., "Influence of food deprivation in the rat on hypothalamic expression of growth hormone-releasing factor and somatostatin," Endocrinology, 127:2111-2116 (1990)). Moreover, expression of GRF is also reduced in animals made obese by ingestion of a high-fat diet compared to GRF expression in normal non-obese animals fed a normal diet (Berelowitz et al. (1992), supra).
When an individual diets, the body compensates with a reduced metabolic rate based on the lower caloric intake. In essence, the body down-regulates the requirement for food, thereby subsisting on less food. As dieting continues, the threshold for caloric intake is reduced. When dieting has ended, the individual typically gains weight while eating a normal diet because of the lowered caloric intake threshold and lower-basal metabolic rate (NIH Technology Assessment Conference Panel, "Methods for voluntary weight loss and control," Ann. Intern. Med., 116:942-949 (1992); Wadden, "Treatment of Obesity by moderate and severe caloric restriction," Ann. Intern. Med., 119:688-693 (1993)).
The reduction in GRF levels in food-deprived rats has been attributed to a lack of dietary protein (Bruno et al., "Regulation of rat hypothalamic prepro-growth hormone-releasing factor messenger ribonucleic acid by dietary protein," Endocrinology, 129:1226-1232 (1991)), which reduction is reversed in part upon supplementation of the diet with the amino acid histidine (Bruno et al., "Regulation of hypothalamic preprogrowth hormone-releasing factor messenger ribonucleic acid expression in food-deprived rats: A role for histaminergic neurotransmission," Endocrinology, 133:1377-1381 (1993)).
Latham and Blundell, "Evidence for the effect of tryptophan on the pattern of food consumption in free feeding and food deprived rats," Life Sciences, 24:1971-1978 (1979), report that intravenous administration of L-tryptophan to rats reduces their overall intake of a normal calorie diet within about 4 hours post-administration of the compound. Thereafter, tryptophan appeared to have little effect on food intake in the rats.
There are available a vast array of diets which purport to be effective in reducing weight in animals, particularly humans. However, while these diets may have resulted in some success regarding weight loss, many of them do not promote long term loss of weight since, unless they are accompanied by ingestion of chemical appetite suppressants, they do not effectively reduce the drive to eat.
The present invention satisfies a long felt need in the art of weight reduction by providing a diet which is specifically designed to concomitantly reduce caloric intake and regulate either, and preferably both the drive to eat and the metabolic effects of dieting, thereby promoting and enhancing long-term weight loss.